Benzodiazepine derivatives are useful compounds for treating various disorders, and include medicaments such as, antiepileptics (imidazo [2,1-b][1,3,5] benzothiadiazepines, U.S. Pat. Nos. 4,444,688; 4,062,852), antibacterials (pyrimido[1,2-c][1,3,5]benzothiadiazepines, GB 1476684), diuretics and hypotensives (pyrrolo(1,2-b)[1,2,5]benzothiadiazepine 5,5 dioxide, U.S. Pat. No. 3,506,646), hypolipidemics (WO 03091232), anti-depressants (U.S. Pat. No. 3,453,266); osteoporosis (JP 2138272).
Recently, it has been shown that cell-binding agent conjugates of indolinobenzodiazepine dimers can inhibit tumor growth both in vitro and in vivo in animal models. See, example, WO 2010/091150, WO 2016/036801, WO 2016/036804. Further, cell-binding agent conjugates of indolinobenzodiazepine dimers that have one imine functionality and one amine functionality have been to shown to display a much higher therapeutic index (ratio of maximum tolerated dose to minimum effective dose) in vivo compared to previously disclosed benzodiazepine derivatives having two imine functionalities. See, for example, WO 2012/128868.
Thus, there exists a need for improved methods for preparing the indolinobenzodiazepine monomer precursors that are more efficient and suitable for large scale manufacturing process for making the cytotoxic indolinobenzodiazepine dimer compounds.